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C. M. Craft, B. M. Brown, L. Rife; Age-Related, Light-Independent Retinal Degeneration in NRL/GRK1 Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3001.
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Retinal degeneration occurs in a pure cone retina model of dark reared NRL/G protein-coupled receptor kinase 1 (GRK1) double knockout (Nrl-/-Grk1-/-) mice compared to Nrl-/-.1 To characterize the environmental influence of light exposure and age progression on maturation and metabolism of cones in Nrl-/-Grk1-/-, further studies were initiated.
Nrl-/- (A Swaroop & AJ Mears), Nrl-/-Arr1-/- (Arr1 -/-, J Chen), Nrl-/-Grk1-/-(Grk1-/-, CK Chen), and Nrl-/-Grk1-/-Arr1-/- mice were born and reared in either total darkness, 12hr:12hr ambient cyclic light, or 8000 lux bright constant light. Retinas were examined at 1, 3, 5, 7 and 9 months by electroretinography (ERG), immunohistochemistry (IHC), and immunoblots. At 1 month, TUNEL assays quantitated retinal apoptotic cell death.
Electrophysiological analyses measured photopic b-wave amplitude of dark-adapted ERG responses elicited by maximum light stimulus. In the 3 lighting conditions tested, with increasing age in Nrl-/-Grk1-/- mice, b-wave amplitude decreases while unchanged in Nrl-/- mice until 7 months. The Nrl-/-Grk1-/- mice cone photoreceptors slowly degenerate with age at a similar rate independent of environmental light exposure with the central inferior region of cones dying first. Immunoblot and IHC analyses reveal a parallel progressive decrease of CARR, UV- and M-opsin pigment expression in the Nrl-/-Grk1-/- mouse retina with increasing age. In contrast, cone protein expression levels remain relatively constant in the cone photoreceptors of the age-matched Nrl-/- mice. TUNEL positive cells were significantly higher in retinas of Nrl-/-Grk1-/- and Nrl-/-Grk1-/-Arr1-/- compared to retinas of Nrl-/- and Nrl-/-Arr1-/.
GRK1 expression is a critical enzyme for maintaining rod and cone photoreceptor light-activated shutoff of the visual pigments. When GRK1 is defective, normal photoreceptor structure and function are compromised. In the Nrl-/-Grk1-/- mouse retina, apoptosis is light-independent and age-related. Our hypothesis is that the age-related retinal degeneration is linked to the absence of GRK1 phosphorylation or other GRK1-dependent functions. Comparative microarray and proteomic analysis will provide clues to the mechanisms that may contribute to this age-related, light-independent cone dystrophy.1 Zhu, X, et al. New Insights into Retinal Degenerative Diseases 2006;133-139
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